Thienopyridines

ABSTRACT

The invention relates to novel thienopyridine derivatives of formula (I), wherein R1, R2, R3, R4 and Y have the meaning cited in claim  1 , are HSP90-inhibitors and can be used for producing a medicament for treating illnesses, wherein the inhibition, regulation and/or modulation of HSP90 plays a roll.

BACKGROUND OF THE INVENTION

The invention was based on the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

The present invention relates to compounds in which the inhibition,regulation and/or modulation of HSP90 plays a role, furthermore topharmaceutical compositions which comprise these compounds, and to theuse of the compounds for the treatment of diseases in which HSP90 playsa role.

The correct folding and conformation of proteins in cells is ensured bymolecular chaperones and is critical for the regulation of theequilibrium between protein synthesis and degradation. Chaperones areimportant for the regulation of many central functions of cells, suchas, for example, cell proliferation and apoptosis (Jolly and Morimoto,2000; Smith et al., 1998; Smith, 2001).

Heat Shock Proteins (HSPs)

The cells of a tissue react to external stress, such as, for example,heat, hypoxia, oxidative stress, or toxic substances, such as heavymetals or alcohols, with activation of a number of chaperones which areknown under the term “heat shock proteins” (HSPs).

The activation of HSPs protects the cell against damage initiated bysuch stress factors, accelerates the restoration of the physiologicalstate and results in a stress-tolerant state of the cell.

Besides this originally discovered protective mechanism promoted by HSPsagainst external stress, further important chaperone functions have alsobeen described in the course of time for individual HSPs under normalstress-free conditions. Thus, various HSPs regulate, for example,correct folding, intracellular localisation and function or regulateddegradation of a number of biologically important proteins of cells.

HSPs form a gene family with individual gene products whose cellularexpression, function and localisation differs in different cells. Thenaming and classification within the family is carried out on the basisof their molecular weight, for example HSP27, HSP70, and HSP90.

Some human diseases are based on incorrect protein folding (see review,for example, Tytell et al., 2001; Smith et al., 1998). The developmentof therapies which engages in the mechanism of the chaperone-dependentprotein folding could therefore be useful in such cases. For example,incorrectly folded proteins result in aggregation of protein withneurodegenerative progression in the case of Alzheimer's disease, priondiseases or Huntington's syndrome. Incorrect protein folding may alsoresult in loss of wild-type function, which can have the consequence ofincorrectly regulated molecular and physiological function.

HSPs are also ascribed great importance in tumour diseases. There are,for example, indications that the expression of certain HSPs correlateswith the stage of progression of tumours (Martin et al., 2000; Conroy etal., 1996; Kawanishi et al., 1999; Jameel et al., 1992; Hoang et al.,2000; Lebeau et al., 1991).

The fact that HSP90 plays a role in a number of central oncogenicsignalling pathways in the cell and certain natural products havingcancer-inhibiting activity target HSP90 has led to the concept thatinhibition of the function of HSP90 would be sensible in the treatmentof tumour diseases.

An HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17AAG), aderivative of geldanamycin, is currently undergoing clinical trials.

HSP90

HSP90 represents approximately 1-2% of the total cellular protein mass.It is usually in the form of a dimer in the cell and is associated witha multiplicity of proteins, so-called co-chaperones (see, for example,Pratt, 1997). HSP90 is essential for the vitality of cells (Young etal., 2001) and plays a key role in the response to cellular stress byinteraction with many proteins whose native folding has been modified byexternal stress, such as, for example, heat shock, in order to restorethe original folding or to prevent aggregation of the proteins (Smith etal., 1998).

There are also indications that HSP90 is of importance as buffer againstthe effects of mutations, presumably through correction of incorrectprotein folding caused by the mutation (Rutherford and Lindquist, 1998).

In addition, HSP90 also has a regulatory importance. Under physiologicalconditions, HSP90, together with its homologue in the endoplasmaticreticulum, GRP94, plays a role in the cell balance for ensuring thestability of the conformation and maturing of various client keyproteins. These can be divided into three groups: receptors for steroidhormones, Ser/Thr or tyrosine kinases (for example ERBB2, RAF-1, CDK4and LCK) and a collection of various proteins, such as, for example,mutated p53 or the catalytic subunit of telomerase hTERT. Each of theseproteins takes on a key role in the regulation of physiological andbiochemical processes of cells. The preserved HSP90 family in humansconsists of four genes, cytosolic HSP90α, the inducible HSP90β isoform(Hickey et al., 1989), GRP94 in the endoplasmatic reticulum (Argon etal., 1999) and HSP75/TRAP1 in the mitochondrial matrix (Felts et al.,2000). It is assumed that all members of the family have a similar modeof action, but, depending on their localisation in the cell, bind todifferent client proteins. For example, ERBB2 is a specific clientprotein of GRP94 (Argon et al., 1999), while the type 1 receptor oftumour necrosis factor (TNFR1) or the retinoblastoma protein (Rb) havebeen found to be clients of TRAP1 (Song et al., 1995; Chen et al.,1996).

HSP90 is involved in a number of complex interactions with a largenumber of client proteins and regulatory proteins (Smith, 2001).Although precise molecular details have not yet been clarified,biochemical experiments and investigations with the aid of X-raycrystallography in recent years have increasingly been able to decipherdetails of the chaperone function of HSP90 (Prodromou et al., 1997;Stebbins et al., 1997). Accordingly, HSP90 is an ATP-dependent molecularchaperone (Prodromou et al, 1997), with dimerisation being important forATP hydrolysis. The binding of ATP results in the formation of atoroidal dimer structure, in which the two N-terminal domains come intoclose contact with one another and act as a switch in the conformation(Prodromou and Pearl, 2000).

Known HSP90 Inhibitors

The first class of HSP90 inhibitors to be discovered were benzoquinoneansamycins with the compounds herbimycin A and geldanamycin. Originally,the reversion of the malignant phenotype in fibroblasts which had beeninduced by transformation with the v-Src oncogene was detected with them(Uehara et al., 1985).

Later, a strong antitumoural activity was demonstrated in vitro (Schulteet al., 1998) and in vivo in animal models (Supko et al., 1995).

Immune precipitation and investigations on affinity matrices then showedthat the principal mechanism of action of geldanamycin involves bindingto HSP90 (Whitesell et al., 1994; Schulte and Neckers, 1998). Inaddition, X-ray crystallographic studies have shown that geldanamycincompetes for the ATP binding site and inhibits the intrinsic ATPaseactivity of HSP90 (Prodromou et al., 1997; Panaretou et al., 1998). Thisprevents the form ation of the multimeric HSP90 complex, with itsproperty of functioning as chaperone for client proteins. As aconsequence, client proteins are degraded via the ubiquitin-proteasomepathway.

The geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin(17AAG) showed an unchanged property in the inhibition of HSP90, thedegradation of client proteins and antitumoural activity in cellcultures and in xenograft tumour models (Schulte et al, 1998; Kelland etal, 1999), but had significantly lower liver cytotoxicity thangeldanamycin (Page et all 1997). 17AAG is currently undergoing phaseI/II clinical trials.

Radicicol, a macrocyclic antibiotic, likewise exhibited revision of thev-Src and v-Ha-Ras-induced malignant phenotype of fibroblasts (Kwon etall 1992; Zhao et al, 1995). Radicicol degrades a large number of signalproteins as a consequence of HSP90 inhibition (Schulte et al., 1998).X-ray crystallographic studies have shown that radicicol likewise bindsto the N-terminal domain of HSP90 and inhibits the intrinsic ATPaseactivity (Roe et al., 1998).

Antibiotics of the coumarine type, as is known, bind to the ATP bindingsite of the HSP90 homolog DNA gyrase in bacteria. The coumarine,Novobiocin, binds to the carboxy-terminal end of HSP90, i.e. to adifferent site in HSP90 than the benzoquinone-ansamycins and radicicol,which bind to the N-terminal end of HSP90 (Marcu et al., 2000b).

The inhibition of HSP90 by novobiocin results in degradation of a largenumber of HSP90-dependent signal proteins (Marcu et al., 2000a).

The degradation of signal proteins, for example ERBB2, was demonstratedusing PU3, an HSP90 inhibitor derived from purines. PU3 causes cellcycle arrest and differentiation in breast cancer cell lines (Chiosis etal., 2001).

HSP90 as Therapeutic Target

Due to the participation of HSP90 in the regulation of a large number ofsignalling pathways which have crucial importance in the phenotype of atumour, and the discovery that certain natural products exert theirbiological effect through inhibition of the activity of HSP90, HSP90 iscurrently being tested as a novel target for the development of a tumourtherapeutic agent (Neckers et al., 1999).

The principal mechanism of action of geldanamycin, 17AAG, and radicicolincludes the inhibition of the binding of ATP to the ATP binding site atthe N-terminal end of the protein and the resultant inhibition of theintrinsic ATPase activity of HSP90 (see, for example, Prodromou et al.,1997; Stebbins et al., 1997; Panaretou et al., 1998). Inhibition of theATPase activity of HSP90 prevents the recruitment of co-chaperones andfavours the formation of an HSP90 heterocomplex, which causes clientproteins to undergo degradation via the ubiquitin-proteasome pathway(see, for example, Neckers et al., 1999; Kelland et al., 1999). Thetreatment of tumour cells with HSP90 inhibitors results in selectivedegradation of important proteins having fundamental importance forprocesses such as cell proliferation, regulation of the cell cycle andapoptosis. These processes are frequently deregulated in tumours (see,for example, Hostein et al., 2001).

An attractive rationale for the development of an inhibitor of HSP90 isthat a strong tumour-therapeutic action can be achieved by simultaneousdegradation of a plurality of proteins which are associated with thetransformed phenotype.

In detail, the present invention relates to compounds which inhibit,regulate and/or modulate HSP90, to compositions which comprise thesecompounds, and to methods for the use thereof for the treatment ofHSP90-induced diseases, such as tumour diseases, viral diseases, suchas, for example, hepatitis B (Waxman, 2002); immune suppression intransplants (Bijlmakers, 2000 and Yorgin, 2000); inflammation-induceddiseases (Bucci, 2000), such as rheumatoid arthritis, asthma, multiplesclerosis, type 1 diabetes, lupus erythematosus, psoriasis andinflammatory bowel disease; cystic fibrosis (Fuller, 2000); diseasesassociated with angiogenesis (Hur, 2002 and Kurebayashi, 2001), such as,for example, diabetic retinopathy, haemangiomas, endometriosis andtumour angiogenesis; infectious diseases; autoimmune diseases;ischaemia; promotion of nerve regeneration (Rosen et al., WO 02/09696;Degranco et al., WO 99/51223; Gold, U.S. Pat. No. 6,210,974 B1);fibrogenetic diseases, such as, for example, sclerorma, polymyositis,systemic lupus, cirrhosis of the liver, keloid formation, interstitialnephritis and pulmonary fibrosis (Strehlow, WO 02/02123).

The invention also relates to the use of the compounds according to theinvention for the protection of normal cells against toxicity caused bychemotherapy, and to the use in diseases where incorrect protein foldingor aggregation is a principal causal factor, such as, for example,scrapie, Creutzfeldt-Jakob disease, Huntington's or Alzheimer's(Sittler, Hum. Mol. Genet., 10, 1307, 2001; Tratzelt et al., Proc. Nat.Acad. Sci., 92, 2944, 1995; Winklhofer et al., J. Biol. Chem., 276,45160, 2001). WO 01/72779 describes purine compounds and the use thereoffor the treatment of GRP94 (homologue or paralogue of HSP90)-induceddiseases, such as tumour diseases, where the cancerous tissue includes asarcoma or carcinoma selected from the group consisting of fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumour,leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, syringocarcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinomas, bone marrow carcinoma, bronchogenic carcinoma,renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonic carcinoma, Wilm's tumour, cervical cancer,testicular tumour, lung carcinoma, small-cell lung carcinoma, bladdercarcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma, leukaemia, lymphoma, multiple myeloma, Waldenström'smacroglobulinaemia and heavy chain disease.

A. Kamal et al. in Trends in Molecular Medicine, Vol. 10 No. 6 Jun.2004, describe therapeutic and diagnostic applications of HSP90activation, inter alia for the treatment of diseases of the centralnervous system and of cardiovascular diseases.

The identification of small compounds which specifically inhibit,regulate and/or modulate HSP90 is therefore desirable and an aim of thepresent invention.

It has been found that the compounds of the formula I and salts thereofhave very valuable pharmacological properties while being welltolerated. In particular, they exhibit HSP90-inhibiting properties.

The present invention therefore relates to compounds of the formula I asmedicaments and/or medicament active ingredients in the treatment and/orprophylaxis of the said diseases and to the use of compounds of theformula I for the preparation of a pharmaceutical for the treatmentand/or prophylaxis of the said diseases and also to a process for thetreatment of the said diseases which comprises the administration of oneor more compounds of the formula I to a patient in need of such anadministration.

The host or patient may belong to any mammal species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, where they provide a model forthe treatment of a human disease.

PRIOR ART

Other pyridothiophene derivatives are described as HSP90 inhibitors inWO 2005/034950 and in WO 2005/021552.

WO 2005/00300 A1 describes triazole derivatives as HSP90 inhibitors.

WO 00/53169 describes HSP90 inhibition with coumarine or a coumarinederivative.

WO 03/041643 A2 discloses HSP90-inhibiting zearalanol derivatives.HSP90-inhibiting pyrazole derivatives which are substituted by anaromatic radical in the 3- or 5-position are disclosed in WO 2004/050087A1 and WO 2004/056782 A1.

WO 03/055860 A1 describes 3,4-diarylpyrazoles as HSP90 inhibitors.Purine derivatives having HSP90-inhibiting properties are disclosed inWO 02/36075 A2.

WO 01/72779 describes purine compounds and the use thereof for thetreatment of GRP94 (homologue or paralogue of HSP90)-induced diseases,such as tumour diseases, where the cancerous tissue includes a sarcomaor carcinoma selected from the group consisting of fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumour,leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, syringocarcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinomas, bone marrow carcinoma, bronchogenic carcinoma,renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonic carcinoma, Wilm's tumour, cervical cancer,testicular tumour, lung carcinoma, small-cell lung carcinoma, bladdercarcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma, leukaemia, lymphoma, multiple myeloma, Waldenström'smacroglobulinaemia and heavy chain disease.

WO 01/72779 furthermore discloses the use of the compounds mentionedtherein for the treatment of viral diseases, where the viral pathogen isselected from the group consisting of hepatitis type A, hepatitis typeB, hepatitis type C, influenza, varicella, adenovirus, herpes simplextype I (HSV-I), herpes simplex type II (HSV-II), cattle plague,rhinovirus, echovirus, rotavirus, respiratory syncytial virus (RSV),papillomavirus, papovavirus, cytomegalovirus, equinovirus, arbovirus,huntavirus, Coxsackie virus, mumps virus, measles virus, rubella virus,polio virus, human immunodeficiency virus type I (HIV-I) and humanimmunodeficiency virus type II (HIV-II).

WO 01/72779 furthermore describes the use of the compounds mentionedtherein for GRP94 modulation, where the modulated biological GRP94activity causes an immune reaction in an individual, protein transportfrom the endoplasmatic reticulum, recovery from hypoxic/anoxic stress,recovery from malnutrition, recovery from heat stress, or combinationsthereof, and/or where the disorder is a type of cancer, an infectiousdisease, a disorder associated with disrupted protein transport from theendoplasmatic reticulum, a disorder associated withischaemia/reperfusion, or combinations thereof, where the disorderassociated with ischaemia/reperfusion is a consequence of cardiacarrest, asystolia and delayed ventricular arrhythmia, heart operation,cardiopulmonary bypass operation, organ transplant, spinal cord trauma,head trauma, stroke, thromboembolic stroke, haemorrhagic stroke,cerebral vasospasm, hypotonia, hypoglycaemia, status epilepticus, anepileptic fit, anxiety, schizophrenia, a neurodegenerative disorder,Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis(ALS) or neonatal stress.

Finally, WO 01/72779 describes the use of an effective amount of a GRP94protein modulator for the preparation of a medicament for changing asubsequent cellular reaction to an ischaemic state in a tissue site inan individual, by treatment of the cells at the tissue site with theGRP94 protein modulator in order that the GRP94 activity in cells isincreased to such an extent that a subsequent cellular reaction to anischaemic state is changed, where the subsequent ischaemic condition ispreferably the consequence of cardiac arrest, asystolia and delayedventricular arrhythmia, heart operation, cardiopulmonary bypassoperation, organ transplant, spinal cord trauma, head trauma, stroke,thromboembolic stroke, haemorrhagic stroke, cerebral vasospasm,hypotonia, hypoglycaemia, status epilepticus, an epileptic fit, anxiety,schizophrenia, a neurodegenerative disorder, Alzheimer's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS) or neonatalstress, or where the tissue site is the donor tissue for a transplant.

Further Literature:

-   Argon Y and Simen B B. 1999 “Grp94, an ER chaperone with protein and    peptide binding properties”, Semin. Cell Dev. Biol., Vol. 10, pp.    495-505.-   Bijlmakers M-J J E, Marsh M. 2000 “Hsp90 is essential for the    synthesis and subsequent membrane association, but not the    maintenance, of the Src-kinase p56lck”, Mol. Biol. Cell, Vol. 11(5),    pp. 1585-1595.-   Bucci M; Roviezzo F; Cicala C; Sessa W C, Cirino G. 2000    “Geldanamycin, an inhibitor of heat shock protein 90 (Hsp90)    mediated signal transduction has anti-inflammatory effects and    interacts with glucocorticoid receptor in vivo”, Brit. J.    Pharmacol., Vol. 131(1), pp. 13-16.-   Carreras C W, Schirmer A, Zhong Z, Santi V S. 2003 “Filter binding    assay for the geldanamycin-heat shock protein 90 interaction”,    Analytical Biochem., Vol. 317, pp 40-46.-   Chen C-F, Chen Y, Dai K D, Chen P-L, Riley D J and Lee W—H. 1996 “A    new member of the hsp90 family of molecular chaperones interacts    with the retinoblastoma protein during mitosis and after heat    shock”, Mol. Cell. Biol., Vol. 16, pp. 4691-4699.-   Chiosis G, Timaul M N, Lucas B, Munster P N, Zheng F F,    Sepp-Lozenzino L and Rosen N. 2001 “A small molecule designed to    bind to the adenine nucleotide pocket of HSP90 causes Her2    degradation and the growth arrest and differentiation of breast    cancer cells”, Chem. Biol., Vol. 8, pp. 289-299.-   Chiosis G, Lucas B, Shtil A, Huezo H, Rosen N 2002 “Development of a    purine-scaffold novel class of HSP90 binders that inhibit the    proliferation of cancer cells and induce the degradation of her2    tyrosine kinase”. Bioorganic Med. Chem., Vol. 10, pp 3555-3564.-   Conroy S E and Latchman D S. 1996 “Do heat shock proteins have a    role in breast cancer?”, Brit. J. Cancer, Vol. 74, pp. 717-721.-   Felts S J, Owen B A L, Nguyen P, Trepel J, Donner D B and Toft D O.    2000 “The HSP90-related protein TRAP1 is a mitochondrial protein    with distinct functional properties”, J. Biol. Chem., Vol. 5, pp.    3305-331 2.-   Fuller W, Cuthbert A W. 2000 “Post-translational disruption of the    delta F508 cystic fibrosis transmembrane conductance regulator    (CFTR)-molecular Chaperone complex with geldanamycin stabilises    delta F508 CFTR in the rabbit reticulocyte lysate”, J. Biol. Chem.,    Vol. 275(48), pp. 37462-37468.-   Hickey E, Brandon S E, Smale G, Lloyd D and Weber L A. 1999    “Sequence and regulation of a gene encoding a human 89-kilodalton    heat shock protein”, Mol. Cell. Biol., Vol. 9, pp. 2615-2626.-   Hoang A T, Huang J, Rudra-Gonguly N, Zheng J, Powell W C, Rabindron    S K, Wu C and Roy-Burman P. 2000 “A novel association between the    human heat shock transcription factor 1 (HSF1) and prostate    adenocarcinoma, Am. J. Pathol., Vol. 156, pp. 857-864.-   Hostein I, Robertson D, Di Stefano F, Workman P and Clarke P A. 2001    “Inhibition of signal transduction by the HSP90 inhibitor    17-allylamino-1 7-demethoxygeldanamycin results in cytostasis and    apoptosis”, Cancer Res., Vol. 61, pp. 4003-4009.-   Hur E, Kim H-H, Choi S M, Kim J H, Yim S, Kwon H J, Choi Y, Kim D K,    Lee M-0, Park H. 2002 “Reduction of hypoxia-induced transcription    through the repression of hypoxia-inducible factor-1α/aryl    hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa    heat-shock protein inhibitor radicicol”, Mol. Pharmacol., Vol.    62(5), pp. 975-982.-   Jameel A, Skilton R A, Campbell T A, Chander S K, Coombes R C and    Luqmani Y A. 1992 “Clinical-   Jolly C and Morimoto R I. 2000 “Role of the heat shock response and    molecular chaperones in oncogenesis and cell death”, J. Natl. Cancer    Inst., Vol. 92, pp. 1564-1572.-   Kawanishi K, Shiozaki H, Doki Y, Sakita I, Inoue M, Yano M,    Tsujinata T, Shamma A and Monden M. 1999 “Prognostic significance of    heat shock proteins 27 and 70 in patients with squamous cell    carcinoma of the esophagus”, Cancer, Vol. 85, pp. 1649-1657.-   Kelland L R, Abel G, McKeage M J, Jones M, Goddard P M, Valenti M,    Murrer B A, and Harrap K R. 1993 “Preclinical antitumour evaluation    of bis-acetalo-amino-dichloro-cyclohexylamine platinum (IV): an    orally active platinum drug”, Cancer Research, Vol. 53, pp.    2581-2586.-   Kelland L R, Sharp S Y, Rogers P M, Myers T G and Workman P. 1999    “DT-diaphorase expression and tumor cell sensitivity to    17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock    protein 90”, J. Natl. Cancer Inst., Vol. 91, pp. 1940-1949.-   Kurebayashi J, Otsuki T, Kurosumi M, Soga S, Akinaga S, Sonoo, H.    2001 “A radicicol derivative, KF58333, inhibits expression of    hypoxia-inducible factor-1α and vascular endothelial growth factor,    angiogenesis and growth of human breast cancer xenografts”, Jap. J.    Cancer Res., Vol. 92(12), 1342-1351.-   Kwon H J, Yoshida M, Abe K, Horinouchi S and Bepple T. 1992    “Radicicol, an agent inducing the reversal of transformed phentoype    of src-transformed fibroblasts, Biosci., Biotechnol., Biochem., Vol.    56, pp. 538-539. Lebeau J, Le Cholony C, Prosperi M T and Goubin G.    1991 “Constitutive overexpression of 89 kDa heat shock protein gene    in the HBL100 mammary cell line converted to a tumorigenic phenotype    by the EJE24 Harvey-ras oncogene”, Oncogene, Vol. 6, pp. 1125-1132.-   Marcu M G, Chadli A, Bouhouche I, Catelli M and Neckers L. 2000a    “The heat shock protein 90 antagonist novobiocin interacts with a    previously unrecognized ATP-binding domain in the carboxyl terminus    of the chaperone”, J. Biol. Chem., Vol. 275, pp. 37181-37186.-   Marcu M G, Schulte T W and Neckers L. 2000b “Novobiocin and related    coumarins and depletion of heat shock protein 90-dependent signaling    proteins”, J. Natl. Cancer Inst., Vol. 92, pp. 242-248.-   Martin K J, Kritzman B M, Price L M, Koh B, Kwan C P, Zhang X,    MacKay A, O'Hare M J, Kaelin C M, Mutter G L, Pardee A B and    Sager R. 2000 “Linking gene expression patterns to therapeutic    groups in breast cancer”, Cancer Res., Vol. 60, pp. 2232-2238.-   Neckers L, Schulte T W and Momnaaugh E. 1999 “Geldanamycin as a    potential anti-cancer agent: its molecular target and biochemical    activity”, Invest. New Drugs, Vol. 17, pp. 361-373.-   Page J, Heath J, Fulton R, Yalkowsky E, Tabibi E, Tomaszewski J,    Smith A and Rodman L. 1997 “Comparison of geldanamycin (NSC-122750)    and 17-allylaminogeldanamycin (NSC-330507D) toxicity in rats”, Proc.    Am. Assoc. Cancer Res., Vol. 38, pp. 308.-   Panaretou B, Prodromou C, Roe S M, OBrien R, Ladbury J E, Piper P W    and Pearl L H. 1998 “ATP binding and hydrolysis are essential to the    function of the HSP90 molecular chaperone in vivo”, EMBO J., Vol.    17, pp. 4829-4836.-   Pratt W B. 1997 “The role of the HSP90-based chaperone system in    signal transduction by nuclear receptors and receptors signalling    via MAP kinase”, Annu. Rev. Pharmacol. Toxicol., Vol. 37, pp.    297-326.-   Prodromou C, Roe S M, O'Brien R, Ladbury J E, Piper P W and Pearl    L H. 1997 “Identification and structural characterisation of the    ATP/ADP-binding site in the HSP90 molecular chaperone”, Cell, Vol.    90, pp. 65-75.-   Prodromou C, Panaretou B, Chohan S, Siligardi G, O'Brien R, Ladbury    J E, Roe S M, Piper P W and Pearl L H. 2000 “The ATPase cycle of    HSP90 drives a molecular “clamp” via transient dimerisation of the    N-terminal domains”, EMBO J., Vol. 19, pp. 4383-4392.-   Roe S M, Prodromou C, O'Brien R, Ladbury J E, Piper P W and Pearl    L H. 1999 “Structural basis for inhibition of the HSP90 molecular    chaperone by the antitumour antibiotics radicicol and    geldanamycin”, J. Med. Chem., Vol. 42, pp. 260-266.-   Rutherford S L and Lindquist S. 1998 “HSP90 as a capacitor for    morphological evolution. Nature, Vol. 396, pp. 336-342.-   Schulte T W, Akinaga S, Murakata T, Agatsuma T, Sugimoto S, Nakano    H, Lee Y S, Simen B B, Argon Y, Felts S, Toft D O, Neckers L M and    Sharma S V. 1999 “Interaction of radicicol with members of the heat    shock protein 90 family of molecular chaperones”, Mol.    Endocrinology, Vol. 13, pp. 1435-1448.-   Schulte T W, Akinaga S, Soga S, Sullivan W, Sensgard B, Toft D and    Neckers L M. 1998 “Antibiotic radicicol binds to the N-terminal    domain of HSP90 and shares important biologic activities with    geldanamcyin”, Cell Stress and Chaperones, Vol. 3, pp. 100-108.-   Schulte T W and Neckers L M. 1998 “The benzoquinone ansamycin    17-allylamino-17-demethoxygeldanamcyin binds to HSP90 and shares    important biologic activities with geldanamycin”, Cancer Chemother.    Pharmacol., Vol. 42, pp. 273-279.-   Smith D F. 2001 “Chaperones in signal transduction”, in: Molecular    chaperones in the cell (P Lund, ed.; Oxford University Press, Oxford    and NY), pp. 165-178.-   Smith D F, Whitesell L and Katsanis E. 1998 “Molecular chaperones:    Biology and prospects for pharmacological intervention”,    Pharmacological Reviews, Vol. 50, pp. 493-513.-   Song H Y, Dunbar J D, Zhang Y X, Guo D and Donner D B. 1995    “Identification of a protein with homology to hsp90 that binds the    type 1 tumour necrosis factor receptor”, J. Biol. Chem., Vol. 270,    pp. 3574-3581.-   Stebbins C E, Russo A, Schneider C, Rosen N, Hartl F U and Pavletich    N P. 1997 “Crystal structure of an HSP90-geldanamycin complex:    targeting of a protein chaperone by an antitumor agent”, Cell, Vol.    89, pp. 239-250.-   Supko J G, Hickman R L, Grever M R and Malspeis L. 1995 “Preclinical    pharmacologic evaluation of geldanamycin as an antitumour agent”,    Cancer Chemother. Pharmacol., Vol. 36, pp. 305-315.-   Tytell M and Hooper P L. 2001 “Heat shock proteins: new keys to the    development of cytoprotective therapies”, Emerging Therapeutic    Targets, Vol. 5, pp. 267-287.-   Uehara U, Hori M, Takeuchi T and Umezawa H. 1986 “Phenotypic change    from transformed to normal induced by benzoquinoid ansamycins    accompanies inactivation of p60src in rat kidney cells infected with    Rous sarcoma virus”, Mol. Cell. Biol., Vol. 6, pp. 21 98-2206.-   Waxman, Lloyd H. Inhibiting hepatitis C virus processing and    replication. (Merck & Co., Inc., USA). PCT Int. Appl. (2002), WO    0207761 Whitesell L, Mimnaugh E G, De Costa B, Myers C E and Neckers    L M. 1994 “Inhibition of heat shock protein HSP90-pp 60v-src    heteroprotein complex formation by benzoquinone ansamycins:    essential role for stress proteins in oncogenic transformation”,    Proc. Natl. Acad. Sci. USA., Vol. 91, pp. 8324-8328.-   Yorgin et al. 2000 “Effects of geldanamycin, a heat-shock protein    90-binding agent, on T cell function and T cell nonreceptor protein    tyrosine kinases”, J. Immunol., Vol. 164(6), pp. 2915-2923.-   Young J C, Moarefi I and Hartl F U. 2001 “HSP90: a specialised but    essential protein-folding tool”, J. Cell. Biol., Vol. 154, pp.    267-273.-   Zhao J F, Nakano H and Sharma S. 1995 “Suppression of RAS and MOS    transformation by radicicol”, Oncogene, Vol. 11, pp. 161-173.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

-   -   in which    -   Y denotes OH, OA, SH, SA, NH₂, NHA, NAA′ or NHR⁵,    -   R¹ denotes Hal, OH, OA, SH, SA, H or A,    -   R², R³ each, independently of one another, denote        —NHCO—(X)_(s)-Q, —CONH—(X)_(s)-Q, —CONA-(X)_(s)-Q,        —NH(CO)NH—(X)_(s)-Q, —NH(CO)O—(X)_(s)-Q, —NHSO₂—(X)_(s)-Q,        —SO₂NH—(X)_(s)-Q, —SO₂NA-(X)_(s)-Q, —(X)_(s)-Q or H,        -   where, if R²≠H, then R³═H or Cl, or        -   if R³≠H, then R²═H or Cl,    -   R⁴ denotes H, Hal, CN, NO₂, A, OH, OA, SH, SA, (CH₂)_(n)COOH,        (CH₂)_(n)COOA, CONH₂, CONHA, CONAA′, NH₂, NHA, NAA′, NHCOOA,        NHCONH₂, NHCONHA, SOA, SO₂A, SO₂NH₂, SO₂NHA and/or SO₂NAA′,    -   two adjacent radicals selected from the group R¹, R², R³, R⁴        -   together also denote methylenedioxy or ethylenedioxy,    -   R⁵ denotes —(CH₂)_(o)-Het¹, —(CH₂)_(o)—NH₂, —(CH₂)_(o)—NHA or        —(CH₂)_(o)—NA₂,    -   A, A′ each, independently of one another, denote unbranched or        branched alkyl having 1-10 C atoms, in which 1-5 H atoms may be        replaced by F, Cl and/or Br,        -   Alk or cyclic alkyl having 3-7 C atoms,    -   A and A′ together also denote an alkylene chain having 2, 3, 4,        5 or 6 C atoms, in which one or two CH₂ groups may be replaced        by O, S, SO, SO₂, NH, NA and/or N—COOA,    -   Alk denotes alkenyl having 2-6 C atoms,    -   X denotes unbranched or branched C₁-C₁₀ alkylene or C₂-C₁₀        alkenylene, each of which is unsubstituted or mono-, di-, tri-        or tetrasubstituted by A, OA, OH, SH, SA, Hal, NO₂, CN, Ar, OAr,        COOH, COOA, CHO, C(═O)A, C(═O)Ar, SO₂A, CONH₂, SO₂NH₂, CONHA,        CONAA′, SO₂NHA, SO₂NAA′, NH₂, NHA, NAA′, OCONH₂, OCONHA,        OCONAA′, NHCOA, NHCOOA, NACOOA, NHSO₂OA, NASO₂OA, NHCONH₂,        NACONH₂, NHCONHA, NACONHA, NHCONAA′, NACONAA′ and/or ═O and in        which one, two or three C groups may be replaced by O, S, SO,        SO₂, NHCO, NACO, CONH, CONA, SO₂NH, SO₂NA, NHSO₂, NASO₂ and/or        by NH groups,    -   Q denotes H, Carb, Ar or Het,    -   Carb denotes cycloalkyl having 3-7 C atoms or cycloalkenyl        having 3-7 C atoms, each of which is unsubstituted or mono-,        di-, tri-, tetra- or pentasubstituted by A, OA, OH, SH, SA, Hal,        NO₂, CN, (CH₂)_(n)Ar′, (CH₂)_(n)COOH, (CH₂)_(n)COOA, CHO, COA,        SO₂A, CONH₂, SO₂NH₂, CONHA, CONAA′, SO₂NHA, SO₂NAA′, NH₂, NHA,        NAA′, OCONH₂, OCONHA, OCONAA′, NHCOA, NHCOOA, NACOOA, NHSO₂OA,        NASO₂OA, NHCONH₂, NACONH₂, NHCONHA, NACONHA, NHCONAA′ and/or        NACONAA′,    -   Ar denotes phenyl, naphthyl or biphenyl, each of which is        unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by        A, OA, OH, SH, SA, Hal, NO₂, CN, (CH₂)_(n)Ar′, (CH₂)_(n)COOH,        (CH₂)_(n)COOA, CHO, COA, SO₂A, CONH₂, SO₂NH₂, CONHA, CONAA′,        SO₂NHA, SO₂NAA′, NH₂, NHA, NAA′, OCONH₂, OCONHA, OCONAA′, NHCOA,        NHCOOA, NACOOA, NHSO₂OA, NASO₂OA, NHCONH₂, NACONH₂, NHCONHA,        NACONHA, NHCONAA′, NACONAA′, NHCO(CH₂)_(n)NH₂ and/or        —O—(CH₂)_(o)-Het¹,    -   Ar′ denotes phenyl, naphthyl or biphenyl, each of which is        unsubstituted or mono-, di- or trisubstituted by A, OA, OH, SH,        SA, Hal, NO₂, CN, (CH₂)_(n)phenyl, (CH₂)_(n)COOH, (CH₂)_(n)COOA,        CHO, COA, SO₂A, CONH₂, SO₂NH₂, CONHA, CONAA′, SO₂NHA, SO₂NAA′,        NH₂, NHA, NAA′, OCONH₂, OCONHA, OCONAA′, NHCOA, NHCOOA, NACOOA,        NHSO₂OA, NASO₂OA, NHCONH₂, NACONH₂, NHCONHA, NACONHA, NHCONAA′        and/or NACONAA′,    -   Het denotes a mono- or bicyclic saturated, unsaturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be mono-, di- or trisubstituted by A, OA, OH, SH, SA, Hal,        NO₂, CN, (CH₂)_(n)Ar′, (CH₂)_(n)COOH, (CH₂)_(n)COOA, CHO, COA,        SO₂A, CONH₂, SO₂NH₂, CONHA, CONAA′, SO₂NHA, SO₂NAA′, NH₂, NHA,        NAA′, OCONH₂, OCONHA, OCONAA′, NHCOA, NHCOOA, NACOOA, NHSO₂OA,        NASO₂OA, NHCONH₂, NACONH₂, NHCONHA, NACONHA, NHCONAA′, NACONAA′,        SO₂A, ═S, ═NH, ═NA and/or ═O (carbonyl oxygen),    -   Het¹ denotes a monocyclic saturated heterocycle having 1 to 2 N        and/or O atoms, which may be mono- or disubstituted by A, OA,        OH, Hal and/or ═O (carbonyl oxygen),    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   o denotes 1, 2, 3 or 4,    -   s denotes 0 or 1,    -   and pharmaceutically usable derivatives, salts, solvates,        tautomers and stereoisomers thereof, including mixtures thereof        in all ratios.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to claims 1-14 and pharmaceutically usable derivatives,solvates, salts, tautomers and stereoisomers thereof, characterised inthat

a) a compound of the formula II

-   -   in which    -   R¹, R² and R³ have the meanings indicated in claim 1,        is reacted with a compound of the formula III        Y—CO—CH₂—  III    -   in which Y has the meaning indicated in claim 1, and    -   Z denotes Cl, Br, I or a free or reactively functionally        modified OH group,        or        b) in that one or more radical(s) R¹, R², R³, R⁴ and/or Y in a        compound of the formula I is (are) converted into one or more        radical(s) R¹, R², R³, R⁴ and/or Y,        by, for example,

-   i) reducing a nitro group to an amino group,

-   ii) hydrolysing an ester group to a carboxyl group,

-   iii) converting an amino group into an alkylated amine by reductive    amination,

-   iv) alkylating and/or acylating a hydroxyl and/or amino group,    and/or a base or acid of the formula I is converted into one of its    salts.

The invention also relates to the hydrates and solvates of thesecompounds. solvates of the compounds are taken to mean adductions ofinert solvent molecules onto the compounds which form owing to theirmutual attractive force. solvates are, for example, mono- or dihydratesor alcoholates.

The compounds of the formula I according to the invention may also existin tautomeric forms. Formula I encompasses all these tautomeric forms.

Pharmaceutically usable derivatives are taken to mean, for example, thesalts of the compounds according to the invention and also so-calledprodrug compounds.

Prodrug derivatives are taken to mean compounds of the formula I whichhave been modified with, for example, alkyl or acyl groups, sugars oroligopeptides and which are rapidly cleaved in the organism to give theeffective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” means the amount of a medicament orpharmaceutical active ingredient that causes a biological or medicalresponse which is sought or desired, for example, by a researcher orphysician in a tissue, system, animal or human.

In addition, the expression “therapeutically effective amount” means anamount which, compared with a corresponding subject who has not receivedthis amount, has the following consequence:

improved healing treatment, healing, prevention or elimination of adisease, a disease picture, a disease state, a complaint, a disorder orof side effects or also the reduction in the progress of a disease, acomplaint or a disorder.

The term “therapeutically effective amount” also encompasses the amountswhich are effective for increasing normal physiological function.

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

For all radicals which occur more than once, their meanings areindependent of one another.

Above and below, the radicals and parameters R¹, R², R³, R⁴ and Y havethe meanings indicated for the formula I, unless expressly indicatedotherwise.

A or A′ preferably denotes alkyl, is unbranched (linear) or branched,and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A or A′ particularlypreferably denotes denotes methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl.

A or A′ very particularly preferably denotes alkyl having 1, 2, 3, 4, 5or 6 C atoms, preferably ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl, furthermore also fluoromethyl, difluoromethylor bromomethyl.

A or A′ also denotes cycloalkyl. Cycloalkyl preferably denotescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A or A′ also denotes Alk. Alk denotes alkenyl having 2-6 C atoms, suchas, for example, vinyl or propenyl.

Cycloalkylalkylene denotes, for example, cyclohexylmethyl,cyclohexylethyl, cyclopentylmethyl or cyclopentylethyl.

C₁-C₁₀ alkylene preferably denotes methylene, ethylene, propylene,butylene, pentylene, hexylene, heptylene, octylene, nonylene ordecylene, isopropylene, isobutylene, sec-butylene, 1-, 2- or3-methylbutylene, 1,1-, 1,2- or 2,2-dimethylpropylene, 1-ethylpropylene,1-, 2-, 3- or 4-methylpentylene, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene,1-ethyl-2-methylpropylene, 1,1,2- or 1,2,2-trimethylpropylene,particularly preferably methylene, ethylene, propylene, butylene,pentylene or hexylene.

Alkenylene denotes a hydrocarbon chain having 2-10 C atoms, having 2free valences and containing at least one double bond.

Ac denotes acetyl, Bzl denotes benzyl, Ms denotes —SO₂CH₃.

Y preferably denotes amino; NHA, preferably methylamino; NAA′,preferably dimethylamino or diethylamino; NHR⁵, preferably—NH—(CH₂)_(o)—NA₂, such as, for example, 2-dimethylaminoethylamino, or—NH—(CH₂)_(o)-Het¹, such as, for example, 2-(morpholin-4-yl)ethylamino.Y particularly preferably denotes NH₂.

R¹ preferably denotes H, OH or OA, such as, for example, methoxy.

R², R³ preferably each, independently of one another, denote—NHCO—(X)_(s)-Q, —CONH—(X)_(s)-Q, —NH(CO)NH—(X)_(s)-Q,—NH(CO)O—(X)_(s)-Q, —(X)_(s)-Q or H,

where, if R²≠H, then R³═H or Cl, or

if R³ #H, then R²═H or Cl.

R⁴ preferably denotes H or Hal, particularly preferably H.

X preferably denotes unbranched or branched C₁-C₁₀ alkylene, which isunsubstituted or mono-, di-, tri- or tetrasubstituted by OA, OH, Hal,COOH, CONH₂, NH₂ and/or NHCOOA and in which one, two or three C groupsmay be replaced by O, NHCO, CONH, SO₂NH, NHSO₂ and/or by NH groups.

Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or paminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m-or p-cyanophenyl, o-, m- or p-ureidophenyl, o-, m- or p-formylphenyl,o-, m- or p-acetylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- orp-carboxyphenyl, o-, m- or p-carboxymethylphenyl, o-, m- orp-carboxymethoxyphenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl,3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-,2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl,2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl,2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar preferably denotes phenyl which is unsubstituted or mono-, di-, tri-,tetra- or pentasubstituted by A, Hal, OA, (CH₂)_(n)COOH, (CH₂)_(n)COOA,NHCO(CH₂)_(n)NH₂ and/or —O—(CH₂)_(o)-Het¹.

Ar particularly preferably denotes phenyl which is unsubstituted ormono- or disubstituted by A, Hal, (CH₂)_(n)COOH, (CH₂)_(n)COOA,NHCO(CH₂)_(n)NH₂ and/or —O—(CH₂)_(o)-Het¹.

Ar′ preferably denotes, for example, phenyl which is unsubstituted ormono-, di- or trisubstituted by Hal.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 3-, 4-, 5-,6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-,4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl,3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals may also be partially or fully hydrogenated.

Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -4- or-5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or-3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het preferably denotes a mono- or bicyclic saturated, unsaturated oraromatic heterocycle having 1 to 4 N, O and/or S atoms, which may bemono-, di- or trisubstituted by A, OA, Hal and/or ═O (carbonyl oxygen).

Het particularly preferably denotes a mono- or bicyclic saturated,unsaturated or aromatic heterocycle having 1 to 2 N and/or O atoms,which may be mono- or disubstituted by A and/or ═O (carbonyl oxygen),where A preferably denotes methyl, ethyl, propyl, butyl, pentyl, hexyl,isopropyl or trifluoromethyl.

In a further embodiment, Het particularly preferably denotes piperidine,piperazine, pyrrolidine, pyridine, pyrrole, indole, indazole, morpholineor isoxazole, each of which is unsubstituted or mono- or disubstitutedby A and/or ═O, where A preferably denotes methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl or trifluoromethyl.

Het¹ preferably denotes a monocyclic saturated heterocycle having 1 to 2N and/or O atoms, which may be mono- or disubstituted by A and/or ═O(carbonyl oxygen), particular preference is given to4-methyl-piperazinyl.

The compounds of the formula I may have one or more chiral centres andtherefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Im, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia Y denotes NH₂ or NHR⁵;-   in Ib R¹ denotes H, OH or OA;-   in Ic R², R³ each, independently of one another, denote    —NHCO—(X)_(s)-Q, —CONH—(X)_(s)-Q, —NH(CO)NH—(X)_(s)-Q,    —NH(CO)O—(X)_(s)-Q, —(X)_(s)-Q or H,    -   where, if R² ≠H, then R³═H or Cl, or    -   if R³ ≠H, then R²═H or Cl;-   in Id R⁴ denotes H or Hal;-   in Ie R⁵ denotes —(CH₂)_(o)-Het¹ or —(CH₂)_(o)—NA₂;-   in If X denotes unbranched or branched C₁-C₁₀ alkylene which is    unsubstituted or mono-, di-, tri- or tetrasubstituted by OA, OH,    Hal, COOH, CONH₂, NH₂ and/or NHCOOA and in which one, two or three C    groups may be replaced by O, NHCO, CONH, SO₂NH, NHSO₂ and/or by NH    groups;-   in Ig Q denotes H, Ar or Het;-   in Ih Ar denotes phenyl which is unsubstituted or mono-, di-, tri-,    tetra- or pentasubstituted by A, Hal, OA, (CH₂)_(n)COOH,    (CH₂)_(n)COOA, NHCO(CH₂)_(n)NH₂ and/or —O—(CH₂)_(o)-Het¹;-   in Ii Het denotes a mono- or bicyclic saturated, unsaturated or    aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be    mono-, di- or trisubstituted by A, OA, Hal and/or ═O (carbonyl    oxygen);-   in Ij Het denotes a mono- or bicyclic saturated, unsaturated or    aromatic heterocycle having 1 to 2 N and/or O atoms, which may be    mono- or disubstituted by A and/or ═O (carbonyl oxygen);-   in Ik Het¹ denotes a monocyclic saturated heterocycle having 1 to 2    N and/or O atoms, which may be mono- or disubstituted by A and/or ═O    (carbonyl oxygen);-   in Il A denotes unbranched or branched alkyl having 1-6 C atoms, in    which 1-5H atoms may be replaced by F and/or Cl;-   in Im Y denotes NH₂ or NHR⁵,    -   R¹ denotes H, OH or OA,    -   R², R³ each, independently of one another, denote        —NHCO—(X)_(s)-Q, —CONH—(X)_(s)-Q, —NH(CO)NH—(X)_(s)-Q,        —NH(CO)O—(X)_(s)-Q, —(X)_(s)-Q or H,    -   where, if R²≠H, then R³═H or Cl, or if R³≠H, then R²═H or Cl,    -   R⁴ denotes H or Hal,    -   R⁵ denotes —(CH₂)_(o)-Het¹ or —(CH₂)_(o)—NA₂,    -   X denotes unbranched or branched C₁-C₁₀ alkylene which is        unsubstituted or mono-, di-, tri- or tetrasubstituted by OA, OH,        Hal, COOH, CONH₂, NH₂ and/or NHCOOA and in which one, two or        three C groups may be replaced by O, NHCO, CONH, SO₂NH, NHSO₂        and/or by NH groups,    -   Q denotes H, Ar or Het,    -   Ar denotes phenyl which is unsubstituted or mono-, di-, tri-,        tetra- or pentasubstituted A, Hal, OA, (CH₂)_(n)COOH,        (CH₂)_(n)COOA, NHCO(CH₂)_(n)NH₂ and/or —O—(CH₂)_(o)-Het¹,    -   Het denotes a mono- or bicyclic saturated, unsaturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be mono-, di- or trisubstituted by A, OA, Hal and/or ═O        (carbonyl oxygen),    -   Het¹ denotes a monocyclic saturated heterocycle having 1 to 2 N        and/or O atoms, which may be mono- or disubstituted by A and/or        ═O (carbonyl oxygen),    -   A denotes unbranched or branched alkyl having 1-6 C atoms, in        which 1-5H atoms may be replaced by F and/or Cl,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   o denotes 1, 2, 3 or 4,    -   s denotes 0 or 1;        and pharmaceutically usable derivatives, solvates, salts,        tautomers and stereoisomers thereof, including mixtures thereof        in all ratios.

The compounds of the formula I are preferably selected from the group

“A35”, “A36”, “A37” and “A38”.

The compounds according to the invention and also the starting materialsfor their preparation are, in addition, prepared by methods known perse, as described in the literature (for example in the standard works,such as Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use may also be made here of variants known per se which are notmentioned here in greater detail.

If desired, the starting materials can also be formed in situ by notisolating them from the reaction mixture, but instead immediatelyconverting them further into the compounds according to the invention.

The starting compounds are generally known. If they are novel, however,they can be prepared by methods known per se.

Compounds of the formula I can preferably be obtained by reacting acompound of the formula II with a compound of the formula III.

The compounds of the formula II and III are generally known. If they arenot know, they can be prepared by methods known per se.

In the compounds of the formula II, Z preferably denotes Cl, Br, I or areactively modified OH group, such as alkylsulfonyloxy having 1-6 Catoms (preferably methylsulfonyloxy) or arylsulfonyloxy having 6-10 Catoms (preferably phenyl- or p-tolylsulfonyloxy). Z particularlypreferably denotes Cl.

The reaction is carried out by methods which are known to the personskilled in the art.

The reaction is preferably carried out under basic conditions. Suitablebases are preferably alkali metal hydroxides, including potassiumhydroxide, sodium hydroxide and lithium hydroxide; alkaline-earth metalhydroxides, such as barium hydroxide and calcium hydroxide; alkali metalalkoxidess, for example potassium ethoxide and sodium propoxide; andvarious organic bases, such as pyridine or diethanolamine.

The reaction is carried out in a suitable inert solvent.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

The solvent is particularly preferably, for example, water and/ortetrahydrofuran.

Depending on the conditions used, the reaction time is between a few 30minutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 130°, in particular between about 30°and about 125°.

It is furthermore possible to convert a compound of the formula I intoanother compound of the formula I by converting one or more radical(s)R¹, R², R³, R⁴ and/or Y into one or more radical(s) R¹, R², R³, R⁴and/or Y, for example by reducing nitro groups to amino groups, forexample by hydrogenation on Raney nickel or Pd/carbon in an inertsolvent, such as methanol or ethanol, and/or

converting an ester group into a carboxyl group and/or

converting an amino group into an alkylated amine by reductive aminationand/or

esterifying carboxyl groups by reaction with alcohols and/or

converting acid chlorides into an acid amide by reaction with an amineand/or

alkylating a hydroxyl group, for example using an alkyl halide.

Furthermore, free amino groups can be acylated in a conventional mannerusing an acid chloride or anhydride ar alkylated using an unsubstitutedor substituted alkyl halide, advantageously in an inert solvent, such asdichloromethane or THF, and/or in the presence of a base, such astriethylamine or pyridine, at temperatures between −60 and +30°.

The compounds of the formulae I can furthermore be obtained byliberating them from their functional derivatives by solvolysis, inparticular hydrolysis, or by hydrogenolysis.

Preferred starting materials for the solvolysis or hydrogenolysis arethose which contain corresponding protected amino and/or hydroxyl groupsinstead of one or more free amino and/or hydroxyl groups, preferablythose which carry an amino-protecting group instead of an H atom bondedto an N atom, for example those which conform to the formula I, butcontain an NHR′ group (in which R′ denotes an amino-protecting group,for example BOC or CBZ) instead of an NH₂ group.

Preference is furthermore given to starting materials which carry ahydroxyl-protecting group instead of the H atom of an hydroxyl group,for example those which conform to the formula I, but contain anR″O-phenyl group (in which R″ denotes an hydroxyl-protecting group)instead of an hydroxyphenyl group.

It is also possible for a plurality of—identical or different—protectedamino and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, they can in many cases be cleaved off selectively.

The term “amino-protecting group” is known in general terms and relatesto groups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but which are easy to remove after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are, in particular, unsubstituted orsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since theamino-protecting groups are removed after the desired reaction (orreaction sequence), their type and size are furthermore not crucial;however, preference is given to those having 1-20, in particular 1-8,carbon atoms. The term “acyl group” is to be understood in the broadestsense in connection with the present process. It includes acyl groupsderived from aliphatic, araliphatic, aromatic or heterocyclic carboxylicacids or sulfonic acids, and, in particular, alkoxycarbonyl,aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of suchacyl groups are alkanoyl, such as acetyl, propionyl and butyryl;aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl;aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl,ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC and2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ (“carbobenzoxy”),4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr, Pbfor Pmc. Preferred amino-protecting groups are BOC and Mtr, furthermoreCBZ, Fmoc, benzyl and acetyl.

The term “hydroxyl-protecting group” is likewise known in general termsand relates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but are easy to remove after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are the above-mentioned unsubstituted orsubstituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.The nature and size of the hydroxyl-protecting groups are not crucialsince they are removed again after the desired chemical reaction orreaction sequence; preference is given to groups having 1-20, inparticular 1-10, carbon atoms. Examples of hydroxyl-protecting groupsare, inter alia, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyland acetyl, where benzyl and tert-butyl are particularly preferred. COOHgroups are preferably protected in the form of their tert-butyl esters.

The compounds of the formula I are liberated from their functionalderivatives—depending on the protecting group used—for example usingstrong acids, advantageously using TFA or perchloric acid, but alsousing other strong inorganic acids, such as hydrochloric acid orsulfuric acid, strong organic carboxylic acids, such as trichloroaceticacid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. Thepresence of an additional inert solvent is possible, but is not alwaysnecessary. Suitable inert solvents are preferably organic, for examplecarboxylic acids, such as acetic acid, ethers, such as tetrahydrofuranor dioxane, amides, such as DMF, halogenated hydrocarbons, such asdichloromethane, furthermore also alcohols, such as methanol, ethanol orisopropanol, and water. Mixtures of the above-mentioned solvents arefurthermore suitable. TFA is preferably used in excess without additionof a further solvent, and perchloric acid is preferably used in the formof a mixture of acetic acid and 70% perchloric acid in the ratio 9:1.The reaction temperatures for the cleavage are advantageously betweenabout 0 and about 50°, preferably between 15 and 300 (room temperature).

The BOC, OBut, Pbf, Pmc and Mtr groups can, for example, preferably becleaved off using TFA in dichloromethane or using approximately 3 to 5NHCl in dioxane at 15-30°, and the FMOC group can be cleaved off using anapproximately 5 to 50% solution of dimethylamine, diethylamine orpiperidine in DMF at 15-30°.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Compounds of the formula I according to the invention may be chiralowing to their molecular structure and may accordingly occur in variousenantiomeric forms. They can therefore exist in racemic or in opticallyactive form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds of the formula I may differ, it may be desirable to usethe enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

The invention furthermore relates to the use of the compounds and/orphysiologically acceptable salts thereof for the preparation of amedicament (pharmaceutical composition), in particular by non-chemicalmethods. They can be converted into a suitable dosage form here togetherwith at least one solid, liquid and/or semi-liquid excipient or adjuvantand, if desired, in combination with one or more further activeingredients.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.1 mg to 3 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the disease conditiontreated, the method of administration and the age, weight and conditionof the patient, or pharmaceutical formulations can be administered inthe form of dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like.

The tablets are formulated by, for example, preparing a powder mixture,granulating or dry-pressing the mixture, adding a lubricant and adisintegrant and pressing the entire mixture to give tablets. A powdermixture is prepared by mixing the compound comminuted in a suitablemanner with a diluent or a base, as described above, and optionally witha binder, such as, for example, carboxymethylcellulose, an alginate,gelatine or polyvinylpyrrolidone, a dissolution retardant, such as, forexample, paraffin, an absorption accelerator, such as, for example, aquaternary salt, and/or an absorbent, such as, for example, bentonite,kaolin or dicalcium phosphate. The powder mixture can be granulated bywetting it with a binder, such as, for example, syrup, starch paste,acadia mucilage or solutions of cellulose or polymer materials andpressing it through a sieve. As an alternative to granulation, thepowder mixture can be run through a tableting machine, giving lumps ofnon-uniform shape which are broken up to form granules. The granules canbe lubricated by addition of stearic acid, a stearate salt, talc ormineral oil in order to prevent sticking to the tablet casting moulds.The lubricated mixture is then pressed to give tablets. The compoundsaccording to the invention can also be combined with a free-flowinginert excipient and then pressed directly to give tablets withoutcarrying out the granulation or dry-pressing steps. A transparent oropaque protective layer consisting of a shellac sealing layer, a layerof sugar or polymer material and a gloss layer of wax may be present.Dyes can be added to these coatings in order to be able to differentiatebetween different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa prespecified amount of the compounds. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and salts, solvates and physiologicallyfunctional derivatives thereof can also be administered in the form ofliposome delivery systems, such as, for example, small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from various phospholipids, such as, forexample, cholesterol, stearylamine or phosphatidylcholines.

The compounds of the formula I and the salts, solvates andphysiologically functional derivatives thereof can also be deliveredusing monoclonal anti-bodies as individual carriers to which thecompound molecules are coupled. The compounds can also be coupled tosoluble polymers as targeted medicament carriers. Such polymers mayencompass polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary.

Injection solutions and suspensions prepared in accordance with therecipe can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the human or animal, the precise disease condition whichrequires treatment, and its severity, the nature of the formulation andthe method of administration, and is ultimately determined by thetreating doctor or vet. However, an effective amount of a compoundaccording to the invention is generally in the range from 0.1 to 100mg/kg of body weight of the recipient (mammal) per day and particularlytypically in the range from 1 to 10 mg/kg of body weight per day. Thus,the actual amount per day for an adult mammal weighing 70 kg is usuallybetween 70 and 700 mg, where this amount can be administered as anindividual dose per day or usually in a series of part-doses (such as,for example, two, three, four, five or six) per day, so that the totaldaily dose is the same. An effective amount of a salt or solvate or of aphysiologically functional derivative thereof can be determined as thefraction of the effective amount of the compound of the formula I perse. It can be assumed that similar doses are suitable for the treatmentof other conditions mentioned above.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient.

Further medicament active ingredients are preferably chemotherapeuticagents, in particular those which inhibit angiogenesis and thus inhibitthe growth and spread of tumour cells; preference is given here to VEGFreceptor inhibitors, including robozymes and antisense which aredirected to VEGF receptors, and angiostatin and endostatin.

Examples of antineoplastic agents which can be used in combination withthe compounds according to the invention generally include alkylatingagents, antimetabolites; epidophyllotoxin; an antineoplastic enzyme; atopoisomerase inhibitor; procarbazin; mitoxantron or platinumcoordination complexes.

Antineoplastic agents are preferably selected from the followingclasses: anthracyclins, vinca medicaments, mitomycins, bleomycins,cytotoxic nucleosides, epothilones, discormolides, pteridines, diynenesand podophyllotoxins.

Particular preference is given in the said classes to, for example,caminomycin, daunorubicin, aminopterin, methotrexate, methopterin,dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil,5-fluorodeoxyuridine monophosphate, cytarabine, 5-azacytidine,thioguanine, azathioprine, adenosine, pentostatin,erythrohydroxynonyladenine, cladribine, 6-mercaptopurine, gemcitabine,cytosinarabinoside, podophyllotoxin or podophyllotoxin derivatives, suchas, for example, etoposide, etoposide phosphate or teniposide,melphalan, vinblastine, vinorelbine, vincristine, leurosidine,vindesine, leurosine, docetaxel and paclitaxel. Other preferredantineoplastic agents are selected from the group discormolide,epothilone D, estramustine, carboplatin, cisplatin, oxaliplatin,cyclophosphamide, bleomycin, gemcitabine, ifosamide, melphalan,hexamethylmelamine, thiotepa, idatrexate, trimetrexate, dacarbazine,L-asparaginase, camptothecin, CPT-11, topotecan, arabinosylcytosine,bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives,interferons and interleukins.

Further medicament active ingredients are preferably antibiotics.Preferred antibiotics are selected from the group

dactinomycin, daunorubicin, idarubicin, epirubicin, mitoxantrone,bleomycin, plicamycin, mitomycin.

Further medicament active ingredients are preferably enzyme inhibitors.Preferred enzyme inhibitors are selected from the group

of the histone deacetylation inhibitors (for example suberoylanilidehydroxamic acid [SAHA]) and the tyrosine kinase inhibitors (for exampleZD 1839 [Iressa]).

Further medicament active ingredients are preferably nuclear exportinhibitors. Nuclear export inhibitors prevent the output of biopolymers(for example RNA) from the cell nucleus. Preferred nuclear exportinhibitors are selected from the group callystatin, leptomycin B,ratjadone.

Further medicament active ingredients are preferably nuclear exportinhibitors. Nuclear export inhibitors prevent the output of biopolymers(for example RNA) from the cell nucleus. Preferred nuclear exportinhibitors are selected from the group callystatin, leptomycin B,ratjadone.

Further medicament active ingredients are preferably immunosuppressants.Preferred immunosuppressants are selected from the group rapamycin,CCl-779 (Wyeth), RAD001 (Novartis), AP23573 (Ariad Pharmaceuticals).

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active ingredient indissolved or lyophilised form.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, in particular for humans, in the treatment of diseases inwhich HSP90 plays a role.

The invention thus relates to the use of compounds of the formula I, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, for the preparation of amedicament for the treatment of diseases in which the inhibition,regulation and/or modulation of HSP90 plays a role.

Preference is given to the use of compounds of the formula I andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, for the preparation of amedicament for the treatment of tumour diseases, for examplefibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumour,leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, syringocarcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinomas, bone marrow carcinoma, bronchogenic carcinoma,renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonic carcinoma, Wilm's tumour, cervical cancer,testicular tumour, lung carcinoma, small-cell lung carcinoma, bladdercarcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, haemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma, leukaemia, lymphoma, multiple myeloma, Waldenström'smacroglobulinaemia and heavy chain disease;

viral diseases, where the viral pathogen is selected from the groupconsisting of hepatitis type A, hepatitis type B, hepatitis type C,influenza, varicella, adenovirus, herpes simplex type I (HSV-I), herpessimplex type II (HSV-II), cattle plague, rhinovirus, echovirus,rotavirus, respiratory syncytial virus (RSV), papillomavirus,papovavirus, cytomegalovirus, echinovirus, arbovirus, huntavirus,Coxsackie virus, mumps virus, measles virus, rubella virus, polio virus,human immunodeficiency virus type I (HIV-I) and human immunodeficiencyvirus type II (HIV-II);for immune suppression in transplants; inflammation-induced diseases,such as rheumatoid arthritis, asthma, multiple sclerosis, type 1diabetes, lupus erythematosus, psoriasis and inflammatory bowel disease;cystic fibrosis; diseases associated with angiogenesis, such as, forexample, diabetic retinopathy, haemangioma, endometriosis, tumourangiogenesis; infectious diseases; autoimmune diseases; ischaemia;promotion of nerve regeneration; fibrogenetic diseases, such as, forexample, sclerorma, polymyositis, systemic lupus, cirrhosis of theliver, keloid formation, interstitial nephritis and pulmonary fibrosis;

The compounds of the formula I can inhibit, in particular, the growth ofcancer, tumour cells and tumour metastases and are therefore suitablefor tumour therapy.

The present invention furthermore encompasses the use of the compoundsof the formula I and/or physiologically acceptable salts and solvatesthereof for the preparation of a medicament for the protection of normalcells against toxicity caused by chemotherapy, and for the treatment ofdiseases in which incorrect protein folding or aggregation is aprincipal causal factor, such as, for example, scrapie,Creutzfeldt-Jakob disease, Huntington's or Alzheimer's.

The invention also relates to the use of the compounds of the formula Iand/or physiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment of diseases of the centralnervous system, of cardiovascular diseases and cachexia.

In a further embodiment, the invention also relates to the use of thecompounds of the formula I and/or physiologically acceptable salts andsolvates thereof for the preparation of a medicament for HSP90modulation, where the modulated biological HSP90 activity causes animmune reaction in an individual, protein transport from theendoplasmatic reticulum, recovery from hypoxic/anoxic stress, recoveryfrom malnutrition, recovery from heat stress, or combinations thereof,and/or where the disorder is a type of cancer, an infectious disease, adisorder associated with disrupted protein transport from theendoplasmatic reticulum, a disorder associated withischaemia/reperfusion, or combinations thereof, where the disorderassociated with ischaemia/reperfusion is a consequence of cardiacarrest, asystolia and delayed ventricular arrhythmia, heart operation,cardiopulmonary bypass operation, organ transplant, spinal cord trauma,head trauma, stroke, thromboembolic stroke, haemorrhagic stroke,cerebral vasospasm, hypotonia, hypoglycaemia, status epilepticus, anepileptic fit, anxiety, schizophrenia, a neurodegenerative disorder,Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis(ALS) or neonatal stress.

In a further embodiment, the invention also relates to the use of thecompounds of the formula I and/or physiologically acceptable salts andsolvates thereof for the preparation of a medicament for the treatmentof ischaemia as a consequence of cardiac arrest, asystolia and delayedventricular arrhythmia, heart operation, cardiopulmonary bypassoperation, organ transplant, spinal cord trauma, head trauma, stroke,thromboembolic stroke, haemorrhagic stroke, cerebral vasospasm,hypotonia, hypoglycaemia, status epilepticus, an epileptic fit, anxiety,schizophrenia, a neurodegenerative disorder, Alzheimer's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS) or neonatalstress.

Test Method for the Measurement of HSP90 Inhibitors

The binding of geldanamycin or 17-allylamino-17-demethoxygeldanamycin(17AAG) to HSP90 and competitive inhibition thereof can be utilised inorder to determine the inhibitory activity of the compounds according tothe invention (Carreras et al. 2003, Chiosis et al. 2002).

In the specific case, a radioligand filter binding test is used. Theradioligand used here is tritium-labelled 17-allylaminogeldanamycin,[3H]17AAG. This filter binding test allows a targeted search forinhibitors which interfere with the ATP binding site.

Material

Recombinant human HSP90α (E. coli expressed, 95% purity); [3H]17AAG(17-allylaminogeldanamycin, [allylamino-2,3-³H. Specific activity:1.11×10¹² Bq/mmol (Moravek, MT-1717);

HEPES filter buffer (50 mM HEPES, pH 7.0, 5 mM MgCl2, BSA 0.01%)Multiscreen FB (1 μm) filter plate (Millipore, MAFBNOB 50).

Method

The 96-well microtitre filter plates are firstly irrigated and coatedwith 0.1% of polyethylenimine.

The test is carried out under the following conditions:

-   Reaction temperature 22° C.-   Reaction time: 30 min., shaking at 800 rpm-   Test volume: 50 μl-   Final Concentrations:-   50 mM HEPES HCl, pH 7.0, 5 mM MgCl2, 0.01% (w/v) BSA-   HSP90:1.5 μg/assay-   [3H]17AAG: 0.08 μM.

At the end of the reaction, the supernatant in the filter plate isremoved by suction with the aid of a vacuum manifold (MultiscreenSeparation System, Millipore), and the filter is washed twice.

The filter plates are then measured in a beta counter (Microbeta,Wallac) with scintillator (Microscint 20, Packard).

“% of control” is determined from the “counts per minutes” values andthe IC-50 value of a compound is calculated therefrom.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: if necessary, water is added,the pH is adjusted, if necessary, to between 2 and 10, depending on theconstitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the product is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent: ethyl acetate/methanol 9:1.

LC-MS Conditions

HP 1100 series Hewlett Packard System having the following features: ionsource: electrospray (positive mode); scan: 100-1000 m/e; fragmentationvoltage: 60 V; gas temperature: 300° C., DAD: 220 nm.

Flow rate: 2.4 ml/min. The splitter used reduced the flow rate for theMS to 0.75 ml/min. after the DAD.

-   Column: Chromolith SpeedROD RP -18e 50-4.6-   Solvent: LiChrosolv quality from Merck KGaA-   Solvent A: H2O (0.01% of TFA)-   Solvent B: ACN (0.008% of TFA)-   Gradient:-   20% of B→100% of B: 0 min to 2.8 min-   100% of B: 2.8 min to 3.3 min-   100% of B→20% of B: 3.3 min to 4 min

The retention times R_(f) [min] and M+H⁺ data MW indicated in thefollowing examples are the measurement results of the LC-MSmeasurements.

EXAMPLE 1

General reaction scheme for the preparation of compounds of the formulaI in which R² denotes an acylated amino group:

Preparation of2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-trifluoromethylbenzoylamino)phenyl]thieno[2,3-b]pyridine(“A1”)

1.1 10.9 g of cyanothioacetamide and 9 ml of 4-methylmorpholine areadded to a solution of 10 g of 4-methoxy-3-nitrobenzaldehyde in 100 mlof ethanol, and the mixture is stirred at room temperature for 48 hours.10% HCl is added to a pH of 5, and the mixture is stirred for a further16 hours. The precipitated material is separated off, washed withethanol and n-heptane and dried, giving 9.6 g of6-amino-3,5-dicyano-4-(4-methoxy-3-nitrophenyl)-2-thioxo-1,2-dihydropyridine(“1”)

1.2 One equivalent of KOH in water is added to a solution of 30.7 g of“1” in 100 ml of DMF. 8.8 g of 2-chloroacetamide are then added, and themixture is stirred for a further hour. A further equivalent of KOH inwater is added, and the mixture is stirred at room temperature for 16hours, subsequently at 100° for a further hour. The mixture is dilutedwith the same amount of water, the precipitated material is separatedoff, washed with water and dried, giving 17 g of2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-nitrophenyl)thieno[2,3-b]pyridine(“2”).

1.3 1.8 of “2” in 100 ml of DMF are hydrogenated by standard methodsusing 5% Pd/C (56% of water) as catalyst. Separation-off of the catalystand removal of the solvent gives [lacuna] g of2-aminocarbonyl-3,6-diamino-5-cyano-4-(3-amino-4-methoxyphenyl)thieno[2,3-b]pyridine(“3”) in quantitative yield,

¹H NMR 250 MHz, DMSO-d₆) δ 15.00 (b), 7.62 (d, 1H), 7.51 (d, 1H), 7.48(d, 1H), 4.06 (s, 3H).

1.4 47 μl of 4-methylmorpholine are added to a solution of 45 μl of3-(trifluoromethyl)benzoyl chloride and 48 mg of 1-hydroxybenzotriazolehydrate in 1 ml of DMF, and the mixture is stirred at room temperaturefor 1 hour. 100 mg of “3” are added, and the mixture is stirred for afurther 16 hours. The mixture is stirred into 10 ml of water, theprecipitated material is separated off, washed with water and purifiedby chromatography (RP flash chromatography; Isco Companion®), giving 24mg of “A”, M+H⁺ 527.50

Analogous reaction of “3” with

-   -   acetyl chloride,    -   trifluoroacetyl chloride,    -   glutaric acid methyl ester chloride,    -   1H-pyridin-2-one-4-carboxylic acid acid chloride,    -   4-methoxycarbonylbenzoyl chloride,    -   methyl chlorocarbonylmethoxyacetate,    -   3-trifluoromethylphenylsulfonyl chloride,        gives the compounds    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-acetamidophenyl)thieno[2,3-b]pyridine        (“A2”), M+H⁺397.43;    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-trifluoroacetamidophenyl)thieno[2,3-b]pyridine        (“A3”), M+H⁺451.40;    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-methoxycarbonylbutyrylamino)phenyl]thieno[2,3-b]pyridine        (“A4a”),    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(1H-pyridin-2-one-4-carbonylamino)phenyl]thieno[2,3-b]pyridine        (“A5”), M+H⁺476.49;    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-methoxycarbonylbenzoylamino)phenyl]thieno[2,3-b]pyridine        (“A6a”),    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-methoxycarbonylmethoxyacetamido)phenyl]thieno[2,3-b]pyridine        (“A7a”),    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-trifluoromethylphenylsulfonamido)phenyl]thieno[2,3-b]pyridine        (“A9”), M+H⁺ 563.55;

EXAMPLE 2

Ester hydrolysis under standard conditions

-   -   of “A4a” gives the compound        2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-carboxybutrylamino)phenyl]thieno[2,3-b]pyridine        (“A4”), M+H⁺469.49;    -   of “A6a” gives the compound        2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-carboxybenzoylamino)phenyl]thieno[2,3-b]pyridine        (“A6”), M+H⁺503.51;    -   of “A7a” gives the compound        2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-carboxymethoxyacetamido)phenyl]thieno[2,3-b]pyridine        (“A7”), M+H⁺471.46.

EXAMPLE 3

82 mg of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride(DAPECI) and 47 μl of 4-methylmorpholine are added to a solution of 55mg of BOC-glycine (BOC-Gly-OH) and 48 mg of 1-hydroxybenzotriazolehydrate in 1 ml of DMF, and the mixture is stirred at room temperaturefor 1 hour. 100 mg of “3” are added, and the mixture is stirred for afurther 16 hours. The mixture is stirred into 10 ml of water, theprecipitated material is separated off and washed with water, giving

-   -   2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tertbutyloxycarbonyl)amino]acetamido}phenyl)thieno[2,3-b]pyridine        (“A10”),

Analogous reaction of “3” with

-   -   BOC-β-Ala-OH (BOC-β-alanine),    -   BOC-GABA-OH (BOC-γ-aminobutyric acid),    -   1H-indole-7-carboxylic acid,    -   BOC-His-OH (BOC-histidine),    -   BOC-Asn-OH (BOC-asparagine),    -   N-(2-carbamoylacetyl)glycine,    -   1H-indazole-7-carboxylic acid,    -   BOC-Ser(O-tert-butyl)-OH (BOC—(S)-serine tert-butyl ether),        gives the compounds

-   2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{3-[(tert-butyloxycarbonyl)amino]propionylamino}phenyl)thieno[2,3-b]pyridine    (“A11”), M+H⁺526.59;    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{4-[(tert-butyloxycarbonyl)amino]butyrylamino}phenyl)thieno[2,3-b]pyridine        (“A12”), M+H⁺540.61;    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(indol-7-ylcarbonylamino)phenyl]thieno[2,3-b]pyridine        (“A13”), M+H⁺498.54;    -   (S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tertbutyloxycarbonyl)amino]-3-(1H-imidazol-4-yl)propionylamino}phenyl)thieno[2,3-b]pyridine        (“A14a”),    -   (S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tertbutyloxycarbonyl)amino]-3-aminocarbonylpropionylamino}phenyl)thieno[2,3-b]pyridine        (“A15a”),    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-[2-(2-carbamoylacetylamino)acetylamino]phenyl]thieno[2,3-b]pyridine        (“A16”), M+H⁺497.51;    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(indazol-7-ylcarbonylamino)phenyl]thieno[2,3-b]pyridine        (“A17”), M+H⁺499.52;    -   (S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tertbutyloxycarbonyl)amino]-3-(tert-butyloxy)propionylamino}phenyl)thieno[2,3-b]pyridine        (“A18a”).

EXAMPLE 4

Removal of the BOC protecting groups from

-   -   A“11”,    -   “A12”,    -   “A14a”,    -   “A15a”,    -   “A18a”,        and cleavage of the tert-butyl ether in HCl/dioxane gives the        compounds    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-amino-propionylamino)phenyl]thieno[2,3-b]pyridine        (“A21”),    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-aminobutyrylamino)phenyl]thieno[2,3-b]pyridine        (“A22”), M+H⁺440.50;    -   (S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-{4-methoxy-3-[2-amino-3-(1H-imidazol-4-yl)propionylamino]phenyl}thieno[2,3-b]pyridine        (“A14”)

-   -   (S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-amino-3-aminocarbonylpropionylamino}phenyl)thieno[2,3-b]pyridine        (“A15”),    -   (S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-amino-3-hydroxypropionylamino)phenyl]thieno[2,3-b]pyridine        (“A18”).

EXAMPLE 5

Reaction of2-aminocarbonyl-3,6-diamino-5-cyano-4-(2-amino-4-methoxyphenyl)thieno[2,3-b]pyridine(“3a”) with 3-trifluoromethylphenyl isocyanate under standard conditionsgives the compound

-   -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-(3-trifluoromethylphenylureido)phenyl]thieno[2,3-b]pyridine        (“A22”).

EXAMPLE 6

Reaction of2-aminocarbonyl-3,6-diamino-5-cyano-4-(2-amino-4-methoxyphenyl)thieno[2,3-b]pyridine(“3a”) analogously to Example 1 with

-   -   benzoyl chloride,    -   3-carbamoylpropionic acid,    -   N-(phenylsulfonyl)glycine,        gives the compounds    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-2-benzoylaminophenyl)thieno[2,3-b]pyridine        (“A8”), M+H⁺459.50;    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-(3-carbamoylpropionylamino)phenyl]thieno[2,3-b]pyridine        (“A19”), M+H⁺454.48;    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-[2-(phenylsulfonyl)acetylamino]phenyl]thieno[2,3-b]pyridine        (“A20”), M+H⁺552.60.

EXAMPLE 7 Preparation of2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-[2-(3-ethylureido)ethylcarbamoyl]phenyl]thieno[2,3-b]pyridine(“A23”)

7.1 Reaction Scheme for the Preparation of the Precursor “A23a”

7.2 A Mixture of “A23a”, “A23b”

palladium(II) acetate (47% of Pd), 1,8-diazabicyclo[5.4.0]undec-7-ene,THF and molybdenum hexacarbonyl is irradiated in the microwave for 1hour at 120°. Conventional work-up gives

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-[2-(3-ethylureido)ethylcarbamoyl]phenyl]thieno[2,3-b]pyridine(“A23”), M+H⁺497.55

Reaction of

with 7-aminoindazole in the presence of Mo(CO)₆ and Pd(OAc)₂ analogouslyto Example 7.2 gives the compound

2-aminocarbonyl-3,6-diamino-5-cyano-4-[3-(indazol-7-ylcarbamoyl)phenyl]thieno[2,3-b]pyridine(“A24”), M+H⁺469.50

Reaction of

with 4-aminobutyramide in the presence of Mo(CO)₆ and Pd(OAc)₂analogously to Example 7.2 gives the compound

-   -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[5-chloro-3-(3-carbamoylpropylcarbamoyl)phenyl]thieno[2,3-b]pyridine        (“A25”), M+H⁺472.93

EXAMPLE 8

PdCl₂(dppf) is added to 3-fluorobenzylzinc bromide (0.5 M in THF), andthe mixture is stirred at room temperature for 5 minutes under an argonatmosphere. A solution of “A26a”

in THF is subsequently added dropwise, and the mixture is stirred at 45°for a further 30 minutes, then at 650 for 1 hour. The mixture is cooled,poured into saturated NH₄Cl solution and subjected to conventionalwork-up, giving2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-fluorobenzyl)phenyl]thieno[2,3-b]pyridine(“A26”), M+H⁺448.49

EXAMPLE 9 9.1 A mixture of “A27a”

2-vinylpyridine, triethylamine, palladium(II) acetate (47% of Pd),tri-o-tolylphosphine and acetonitrile is irradiated in the microwave at160° for 30 minutes. Toluene is added to the reaction mixture, which isextracted a number of times with water. The organic phase is dried andevaporated. The product is purified by chromatography (ISCO/40 g column;petroleum ether/ethyl acetate: 4/1 to 1/1), giving “A27b”

9.2 A mixture of “A27b”, 5% Pd/C (56% of water) and THF is hydrogenatedfor 16 hours at 1.4 bar and room temperature in a BÜCHI apparatus.removal of the catalyst and removal of the solvent gives2-aminocarbonyl-3,6-diamino-5-cyano-4-[3-chloro-4-methoxy-2-[2-(pyridin-2-yl)ethyl]phenyl]thieno[2,3-b]pyridine(“A27”), M+H⁺497.96

Reaction of “A26a” with methyl acrylate analogously to Example 9.1 givesthe compound “A28a”

and hydrogenation thereof analogously to Example 9.2 and ester cleavagegives the compound

-   -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-carboxyethyl)phenyl]thieno[2,3-b]pyridine        (“A28”), M+H⁺412.44

EXAMPLE 10

A mixture of “A26a”, “A29a”

propanol, palladium(II) acetate, triphenylphosphine, sodium carbonatesolution and water is heated for 16 hours under an N₂ atmosphere andunder reflux in a Suzuki reaction. The mixture is cooled, subjected toconventional work-up, giving the compound

-   -   2-aminocarbonyl-3,6-diamino-5-cyano-4-{4-methoxy-3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}thieno[2,3-b]pyridine        (“A29”), M+H⁺558.68

EXAMPLE 11

Reaction of “A30a”

with “A30b”

analogously to Example 10 gives the compound2-aminocarbonyl-3,6-diamino-5-cyano-4-{4-methoxy-3-[3-(2-aminoacetylamino)phenyl]phenyl}-thieno[2,3-b]pyridine(“A30”), M+H⁺559.66

EXAMPLE 12

Reaction of “A31a”

with glutaric acid methyl ester chloride analogously to Example 1 givesthe compound “A31b”

-   -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-chloro-2-(4-methoxycarbonylbutyrylamino)phenyl]thieno[2,3-b]pyridine        (“A31b”).

Ester cleavage thereof gives2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-chloro-2-(4-carboxybutyrylamino)phenyl]thieno[2,3-b]pyridine(“A31”), M+H⁺503.94

EXAMPLE 13

Reaction of “A32a”

with “A32b”

analogously to Example 1 gives the compound “A32”2-aminocarbonyl-3,6-diamino-5-cyano-4-[2-chloro-4-difluoromethoxy-3-[3-(4-methylpiperazin-1-yl)propionylamino]phenyl]thieno[2,3-b]pyridine(“A32”), M+H⁺580.03

EXAMPLE 14

Reaction of “A33a”

with glutaric acid methyl ester chloride analogously to Example 1 givesthe compound “A33b”

Ester cleavage thereof gives2-(2-morpholin-4-ylethylcarbamoyl)-3,6-diamino-5-cyano-4-[2-(4-carboxybutyrylamino)phenyl]thieno[2,3-b]pyridine(“A33”), M+H⁺552.63.

EXAMPLE 15

Reaction of “A34a”

with benzyl alcohol under standard conditions gives the compound2-aminocarbonyl-3,6-diamino-5-cyano-4-[2-(benzyloxycarbonylamino)phenyl]thieno[2,3-b]pyridine(“A34”), M+H⁺489.53 (“A34”)

EXAMPLE 16

The following compounds are obtained analogously to the preparation of“A1”

-   -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-trifluoromethylbenzoylamino)phenyl]thieno[2,3-b]pyridine        (“A35”),

¹H NMR 250 MHz, DMSO-d₆) δ 9.99 (b), 8.16 (d, 1H), 7.92 (d, 2H), 7.37(d, 2H), 7.02 (s, 1H), 5.90 (s, 1H), 3.96 (s, 3H);

-   -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-trifluoromethylbenzoylamino)phenyl]thieno[2,3-b]pyridine        (“A36”).

The compounds

-   -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(pyridin-4-ylcarbonylamino)phenyl]thieno[2,3-b]pyridine        (“A37”),    -   2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(prop-2-ylcarbonylamino)phenyl]thieno[2,3-b]pyridine        (“A38”),        are obtained analogously to the preparation of “A17”.        Pharmacological Data

Affinity to receptors

TABLE 1 Compound No. HSP90-IC₅₀ [M] “A35” 5.9 × 10⁻⁶ “A36” 1.1 × 10⁻⁵“A37” 1.9 × 10⁻⁶ “A38” 5.5 × 10⁻⁶

The following examples relate to pharmaceutical compositions:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient according to the inventionand g of disodium hydrogenphosphate in 3 l of bidistilled water isadjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered,transferred into injection vials, lyophilised under sterile conditionsand sealed under sterile conditions. Each injection vial contains 5 mgof active ingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient according to the inventionwith 100 g of soya lecithin and 1400 g of cocoa butter is melted, pouredinto moulds and allowed to cool. Each suppository contains 20 mg ofactive ingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient according to theinvention, 9.38 g of NaH₂PO₄ 2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient according to the invention are mixed with99.5 g of Vaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient according to the invention, 4 kgof lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg ofmagnesium stearate is pressed in a conventional manner to give tabletsin such a way that each tablet contains 10 mg of active ingredient.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient according to the invention are introduced intohard gelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of an active ingredient according to the invention in60 l of bidistilled water is sterile filtered, transferred intoampoules, lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. A compound which is2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-trifluoromethylbenzoylamino)phenyl]thieno[2,3-b]pyridine(“A1”),2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-acetamidophenyl)thieno[2,3-b]pyridine(“A2”),2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-trifluoroacetamidophenyl)thieno[2,3-b]pyridine(“A3”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-methoxycarbonylbutyrylamino)phenyl]thieno[2,3-b]pyridine(“A4a”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(1H-pyridin-2-one-4-carbonylamino)phenyl]thieno[2,3-b]pyridine(“A5”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-methoxycarbonylbenzoylamino)phenyl]thieno[2,3-b]pyridine(“A6a”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-methoxycarbonylmethoxyacetamido)phenyl]thieno[2,3-b]pyridine(“A7a”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-trifluoromethylphenylsulfonamido)phenyl]thieno[2,3-b]pyridine(“A9”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-carboxybutrylamino)phenyl]thieno[2,3-b]pyridine(“A4”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-carboxybenzoylamino)phenyl]thieno[2,3-b]pyridine(“A6”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-carboxymethoxyacetamido)phenyl]thieno[2,3-b]pyridine(“A7”),2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tert-butyloxycarbonyl)amino]acetamido}phenyl)thieno[2,3-b]pyridine(“A10”),2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{3-[(tert-butyloxycarbonyl)amino]propionylamino}phenyl)thieno[2,3-b]pyridine(“A11”),2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{4-[(tert-butyloxycarbonyl)amino]butyrylamino}phenyl)thieno[2,3-b]pyridine(“A12”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(indol-7-ylcarbonylamino)phenyl]thieno[2,3-b]pyridine(“A13”),(S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tert-butyloxycarbonyl)amino]-3-(1H-imidazol-4-yl)propionylamino}phenyl)thieno[2,3-b]pyridine(“A14a”),(S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tert-butyloxycarbonyl)amino]-3-aminocarbonylpropionylamino}phenyl)thieno[2,3-b]pyridine(“A15a”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-[2-(2-carbamoylacetylamino)acetylamino]phenyl]thieno[2,3-b]pyridine(“A16”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(indazol-7-ylcarbonylamino)phenyl]thieno[2,3-b]pyridine(“A17”),(S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tert-butyloxycarbonyl)amino]-3-(tert-butyloxy)propionylamino}phenyl)thieno[2,3-b]pyridine(“A18a”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-aminopropionylamino)phenyl]thieno[2,3-b]pyridine(“A21”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-aminobutyrylamino)phenyl]-aminocarbonyl-3,6-diamino-5-cyano-4-{4-methoxy-3-[2-amino-3-(1H-imidazol-4-yl)propionylamino]phenyl}thieno[2,3-b]pyridine(“A14”),(S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-amino-3-aminocarbonylpropionylamino}phenyl)thieno[2,3-b]pyridine(“A15”),(S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-amino-3-hydroxypropionylamino)phenyl]thieno[2,3-b]pyridine(“A18”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-(3-trifluoromethylphenylureido)phenyl]thieno[2,3-b]pyridine(“A22”),2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-2-benzoylaminophenyl)thieno[2,3-b]pyridine(“A8”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-(3-carbamoylpropionylamino)phenyl]thieno[2,3-b]pyridine(“A19”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-[2-(phenylsulfonyl)acetylamino]phenyl]thieno[2,3-b]pyridine(“A20”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-[2-(3-ethylureido)ethylcarbamoyl]phenyl]thieno[2,3-b]pyridine(“A23”), 2-aminocarbonyl-3,6-diamino-5-cyano-4-[3-(indazol-7-ylcarbamoyl)phenyl]thieno[2,3-b]pyridine (“A24”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[5-chloro-3-(3-carbamoylpropylcarbamoyl)phenyl]thieno[2,3-b]pyridine(“A25”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-fluorobenzyl)phenyl]thieno[2,3-b]pyridine(“A26”),2-aminocarbonyl-3,6-diamino-5-cyano-4-{3-chloro-4-methoxy-2-[2-(pyridin-2-yl)ethyl]phenyl}thieno[2,3-b]pyridine(“A27”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-carboxyethyl)phenyl]thieno[2,3-b]pyridine(“A28”),2-aminocarbonyl-3,6-diamino-5-cyano-4-{4-methoxy-3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}thieno[2,3-b]pyridine(“A29”),2-aminocarbonyl-3,6-diamino-5-cyano-4-{4-methoxy-3-[3-(2-aminoacetylamino)phenyl]phenyl}thieno[2,3-b]pyridine(“A30”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-chloro-2-(4-methoxycarbonylbutyrylamino)phenyl]thieno[2,3-b]pyridine(“A31b”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-chloro-2-(4-carboxybutyrylamino)phenyl]thieno[2,3-b]pyridine(“A31”),2-aminocarbonyl-3,6-diamino-5-cyano-4-{2-chloro-4-difluoromethoxy-3-[3-(4-methylpiperazin-1-yl)propionylamino]phenyl}thieno[2,3-b]pyridine(“A32”),2-(2-morpholin-4-ylethylcarbamoyl)-3,6-diamino-5-cyano-4-[2-(4-carboxybutyrylamino)phenyl]-thieno[2,3-b]pyridine(“A33”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[2-(benzyloxycarbonylamino)phenyl]thieno[2,3-b]pyridine(“A34”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-trifluoro-methylbenzoylamino)phenyl]thieno[2,3-b]pyridine(“A35”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-tri-fluoromethylbenzoylamino)phenyl]thieno[2,3-b]pyridine(“A36”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(pyridin-4-ylcarbonylamino)phenyl]-thieno[2,3-b]pyridine(“A37”),2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(prop-2-ylcarbonylamino)phenyl]-thieno[2,3-b]pyridine(“A38”), or a salt, tautomer or stereoisomer thereof, including mixturesthereof in all ratios.